Substituted quinazoline or pyridopyrimidine derivative

Abstract

The present invention provides a compound having a glucokinase activating action being useful for prevention or treatment of diabetes mellitus, etc. being represented by the formula (I): X is nitrogen atom, etc.; Y is oxygen atom, etc.; R 1 is an optionally substituted five to six-membered heteroaryl group, etc.; R 2 is hydrogen atom or fluorine atom; and ring A is a monocyclic or bicyclic heteroaryl group which may have a substituent represented by the formula (II)] or a pharmaceutically acceptable salt thereof.

1. A compound represented by the formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is CH; 
 Y is oxygen atom or sulfur atom; 
 R 1  is one group or atom optionally selected from the following (1), (2), (3), (4), (5) and (6):
 (1) a five- or six-membered heteroaryl group having one to three hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom in a ring, said heteroaryl group (1) being optionally fused to a phenyl ring; 
 (2) an aryl group; 
 (3) a straight-chain or branched lower alkyl group; 
 (4) a cycloalkyl group having 3 to 7 carbon atoms; 
 
 
       one of the carbon atoms contained in said group except for a carbon atom bonding to Y, being optionally replaced with an oxygen atom, NH, N-alkanoyl group or carbonyloxy group said R 1  may have one to three groups, being the same or different, selected from α;
 R 2  is hydrogen atom or fluorine atom; 
 ring A is a monocyclic or bicyclic heteroaryl group represented by the formula (II): 
 
       
         
           
           
               
               
           
         
       
       said ring A optionally having one to three substituent groups selected from β;
 substituent group α is selected from the group consisting of:
 a lower alkyl group optionally substituted with one to three halogen atom(s); 
 a cycloalkyl group having 3 to 7 carbons; 
 a lower alkoxy group; 
 a hydroxyl group; 
 a hydroxyalkyl group; 
 
 said hydrogen atom of the hydroxyl portion of the hydroxyalkyl group being optionally substituted with a lower alkyl group;
 an alkanoyl group; 
 halogen atom; 
 oxy group; 
 a lower alkylsulfonyl group; 
 a lower alkylsulfonylamino group; 
 a mono- or di-lower alkylcarbamoyl group; 
 a mono- or di-lower alkylcarbamoylalkyl group; 
 a mono- or di-lower alkylsulfamoyl group; 
 an amino group; 
 a mono- or di-lower alkylamino group; 
 cyano group; and
 a five- or six-membered heteroaryl group which may have one to three hetero atom(s) selected from the group consisting of nitrogen, sulfur and oxygen; 
 
 
 substituent group β is selected from the group consisting of:
 a lower alkyl group; 
 a lower alkoxy group; 
 a halogen atom; 
 a trifluoromethyl group; 
 a hydroxyalkyl group; 
 
 wherein the hydrogen atom of hydroxyl group in said hydroxyalkyl group may he substituted with a lower alkyl group;
 an aminoalkyl group; 
 
 and wherein the amino group in said aminoalkyl group may be further substituted with a lower alkyl group;
 an alkanoyl group; 
 carboxyl group; 
 
 an alkoxycarbonyl group; and
 a cyano group. 
 
 
     
     
       2. A compound or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein R 1  is a group which is optionally selected from the following (1) and (2):
 (1) a five- or six-membered heteroaryl group having one to three hetero atom(s) selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom in a ring; said heteroaryl group may form a fused ring with phenyl group; and 
 (2) an aryl group; 
 
       said R 1  may have one to three group(s), being same or different, selected from the above-mentioned substituent group α. 
     
     
       3. A compound or a pharmaceutically acceptable salt thereof according to  claim 2 , wherein the ring A is selected from the group consisting of: thiazolo[5,4-b]pyridinyl, pyrazinyl, thiadiazolyl and pyrazolyl which may have one to three substituent(s), being same or different, selected from the substituent group β. 
     
     
       4. A compound or a pharmaceutically acceptable salt thereof according to  claim 3 , wherein Y represents a sulfur atom. 
     
     
       5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
 [6-(4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 (6-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-thiazol-2-yl-amine, 
 [6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]-pyrazin-2-yl -amine, 
 (6-phenoxy-quinazolin-4-yl)-pyrazin-2-yl-amine, 
 [6-(4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl-pyrazin-2-yl-amine, 
 [6-(4-methyl-4H-[1,2,4]triazole-3-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 (6-phenoxy-quinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(2-fluoro-phenoxy)-quinazolin-4-yl]thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(1-methyl-1H-imidazol-2-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(pyridin-2-ylsulfanyl)-quinazolin-4-yl]-thiazolo-[5,4-b]pyridin-2-yl-amine, 
 [6-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-(3-methyl-[1,2,4]thiadiazol-5-yl-amine, 
 [6-(pyrimidin-2-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-thiazolo[4,5-b]pyrazin-2-yl-amine, 
 benzothiazol-2-yl-[6-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-amine, 
 [6-(3H-[1,2,3]triazol-4-ylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl -amine, 
 (1-methyl-1H-pyrazol-3-yl)-[6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]-amine, 
 [6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]-pyrimidin-4-yl-amine, 
 (5-methyl-pyrazin-2-yl)-[6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]amine, 
 [6-(4-methyl-4H-1-[1,2,4]triazol-3-ylsulfanyl)-quinazolin-4-yl]-pyrazin-2-yl-amine, 
 (5-chloro-thiazol-2-yl)-[6-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-quinazolin-4-yl]-amine, 
 [6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 (6-isopropoxy-quinazolin-4-yl)-pyrazin-2-yl-amine, 
 (6-isopropoxy-quinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(2-hydroxy-(1S)-methyl-ethoxy-quinazolin-4-yl)]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 (6-cyclopentyloxy-quinazolin-4-yl)-thiazolo[5,4-b]-pyridin-2-yl-amine, 
 [6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazolin-4-yl]-isoxazol-3-yl-amine, 
 [6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazolin-4-yl]-(5-fluoro-thiazolo-[5,4-b]pyridin-2-yl)-amine, 
 [6-(2-fluoro-1-fluoromethyl-ethoxy)-quinazolin-4-yl]-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-amine, 
 (6-methoxy-quinazolin-4-yl)-pyrazin-2-yl-amine, 
 (6-hydroxy-quinazolin-4-yl)-thiazolo[5,4-b]-pyridin-2-yl-amine, 
 (4-methyl-1,3-thiazol-2-yl)-6-(4-methyl-1,2,4-triazol-3-ylsulfanyl)-quinazolin-4-yl-amine, 
 (5-methyl-1,3-thiazol-2-yl)-6-(4-methyl-1,2,4-triazol-3-ylsulfanyl)-quinazolin-4-yl-amine, 
 6-(methylbenzoate-2-yl)sulfanyl-thiazolo[5,4-b]-pyridin-2-ylquinazolin-4-yl-amine, 
 6-(2-hydroxymethylphenylsulfanyl)-thiazolo[5,4-b]-pyridin-2-ylquinazolin-4-yl-amine, 
 6-(pyrazin-2-ylsulfanyl)-thiazolo[5,4-b]pyridin-2-ylquinazolin-4-yl-amine, 
 6-(3-fluoropyridiin-2-ylsulfanyl)-thiazolo[5,4-b]-pyridin-2-ylquinazolin-4-yl-amine 
 6-(benzoate-2-ylsulfanyl)-thiazolo[5,4-b]pyridin-2-ylquinazolin-4-yl-amine, 
 6-(3-chloropyridin-2-ylsulfanyl)-(1-methylpyrazol-3-yl)quinazolin-4-yl-amine, 
 [6-(2-dimethylamino-ethylsulfanyl)-quinazolin-4-yl]-thiazolo-[5,4-b]pyridin-2-yl-amine, 
 [6-(cyclopentylsulfanyl)-quinazolin-4-yl]-thiazolo-[5,4-b]pyridin-4-yl-amine, 
 [6-(2-fluorophenylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]-pyridin-2-yl -amine, 
 [6-(2-methoxyphenylsulfanyl)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(3-chloropyridin-2-yloxy)-quinazolin-4-yl]-thiazolo[5,4-b]-pyridin-2-yl-amine, 
 [6-(3-cyanopyridin-2-yloxy)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(3-carboxamidopyridin-2-yloxy)-quinzaolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(pyridin-2-yloxy)-quinazolin-4-yl]-thiazolo-[5,4-b]pyridin-2-yl-amine, 
 [6-(3-methylpyridin-2-yloxy)-quinzaolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(methylcarbamoyl-methyloxy)-quinazolin-4-yl]-thiazolo-[5,4-b]pyridin-2-yl-amine, 
 [6-(3-methylsulfonylpyridin-2-yloxy)-quinazolin-4-yl]-thiazolo[5,4-b]pyridin-2-yl-amine, 
 [6-(3-chloropyridin-2-yloxy)-quinazolin-4-yl]-3-methyl-[1,2,4]thiadiazol-5-yl-amine, 
 [6-(3-fluoropyridin-2-yloxy)-quinazolin-4-yl]-3-methyl-[1,2,4]thiadiazol-5-yl-amine, 
 [6-(3-chloropyridin-2-yloxy)-quinazolin-4-yl]-pyridin-2-yl-amine, 
 [6-(tetrahydro-2H-pyran-4-yloxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine 
 [6-(3,5-difluoropyridin-2-yloxy)-quinazolin-4-yl]-3-methyl-[1,2,4]thiadiazol-5-yl-amine, 
 [6-(2-chloro-6-(methylsulfonyl)phenoxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2,4-difluorophenoxy)-quinazolin-4-yl](1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2-fluoro-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-phenoxy)-quinazolin-4-yl]-3-methyl-[1,2,4]-thiadiazol-5-yl-amine, 
 [6-(2-fluoro-4-(methylsulfonyl)phenoxy)-quinazolin-4-yl-3-methyl-[1,2,4]thiadiazol-5-yl-amine, 
 [6-(2-fluoro-6-(methylsulfonyl)phenoxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2-fluoro-6-(methylsulfonyl)phenoxy)-quinazolin-4-yl]-(1-ethyl-1H-pyrazol-3-yl)-amine, 
 [6-(2-fluoro-6-(methylsulfonyl)-phenoxy)-quinazolin-4-yl]-pyrazin-2-yl-amine, 
 [6-(2-chloro-6-(methanesulfonylamino)phenoxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 3-fluoro-2-({4-[(pyrazin-2-yl)amino]quinazolin-6-yl}oxy)benzonitrile, 
 [6-(butyllacton-2-yloxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2,4-difluoro-6-(methylsulfonyl)phenoxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(2-fluoro-6-(methylsulfonyl)phenoxy)-quinazolin-4-yl]-thiazolo[5,4-b]-pyridin-2-yl-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-[2-(methylsulfonyl)-phenoxy]quinazolin-6-yl-amine, 
 3-fluoro-2-({4-[(5-methylpyrazin-2-yl)amino]-quinazolin-6-yl}oxy)benzonitrile, 
 6-(3-chloropyridin-2-ylsulfanyl)-(1-methylpyrazol-3-yl)quinazolin-4-yl-amine, 
 6-(3-chloropyridin-2-ylsulfanyl)-(5-methyl-pyrazin-2-yl)quinazolin-4-yl-amine, 
 6-(3-choropyridin-2-ylsulfanyl)-(1H-pyrazol-3-yl)-quinazolin-4-yl-amine, 
 6-(acetylpiperidin-4-yl)oxy-N-[1,3]-thiazolo[5,4-d]-pyridin-2-ylquinazolin-4-yl-amine, 
 N-(1-methyl-1H-1-pyrazol-3-yl)-6-(pyrazin-2-yloxy)-quinazolin-4-yl-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-(pyrimidin-4-yloxy)-quinazolin-4-yl-amine, 
 6-[2-fluoro-1-(fluoromethyl)ethoxy]-N-[1 ,3]thiazol-[5,4-d]pyrimidin-2-ylquinazolin-4-yl-amine, 
 6-[(3-chloropyridin-2-yl)oxy]-N-1,3-thiazol-2-ylquinazolin-4-amine, 
 (1-methylpyrazol-3-yl)quinazolin-4-yl-amine, 
 6-(1,3-benzothiazol-2-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)-quinazolin-4-yJ-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-(quinazolin-2-yloxy)-quinazolin-4-yl-amine, 
 6-[(5-fluoropyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 6-[(3-chloropyridin-2-yl)oxy]-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-(pyridin-3-yloxy)-quinazolin-4-yl-amine, 
 6-[(3-chloropyridin-2-yl)oxy]-N-4H-[1,2,4]-triazol-3-ylquinazolin-4-yl-amine, 
 6-[(5-fluoropyridin-3-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 6-[(3-chloropyridin-2-yl)oxy]-N-[1,2,4]-thiadiazol-5-ylquinazolin-4-yl-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-[(3-methylpyridin-2-yl)oxy]quinazolin-4-yl-amine, 
 6-{[3-(difluoromethyl)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 N-(1-methyl-1H-pyrazol-3-yl)-6-{[3-(trifluoromethyl)-pyridin-2-yl]oxy}quinazolin-4-yl-amine, 
 [2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]methanol, 
 6-{[3-(fluoromethyl)-pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 1-[2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]-quinazolin-6-yl}oxy)pyridin-3-yl]ethanone, 
 5-chloro-2-methyl-4-({4-[(1-methyl-1H-pyrazol-3-yl)-amino]quinazolin-6-yl}oxy)pyridazin-3(2H)-one, 
 6-[(6-fluoropyridin-2-yl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 [3-fluoro-2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)phenyl]methanol, 
 6-[2-fluoro-6-(fluoromethyl)-phenoxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 [3-chloro-4-({4-[(1-methyl-1H-pyrazol-3-yl)amino]-quinazolin-6-yl}oxy)phenyl]methanol, 
 Methyl 5-(methylsulfonyl)-2-({4-[(3-methyl-[1,2,4]-thiadiazol-5-yl)amino]-quinazolin-6-yl}oxy)benzoate, 
 3-fluoro-2-({4-[(1-pyridin-2-yl-1H-pyrazol-3-yl)-amino]quinazolin-6-yl}oxy)benzonitrile, 
 1-[3-fluoro-2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]-quinazolin-6-yl}oxy)phenyl]ethanone, 
 6-[(3-chloropyridin-2-yl)oxy]-N-[1-(difluoromethyl)-1H-pyrazol-3-yl]quinazolin-4-yl-amine, 
 3-chloro-N,N-dimethyl-2-({4-[(3-methyl-[1,2,4]-thiadiazol-5-yl)amino]quinazolin-6-yl}oxy)benzenesulfon-amide, 
 6-[2-chloro-6-(ethylsulfonyl)phenoxy]-N-(3-methyl-1,2,4-thiadiazol-5-yl)quinazolin-4-yl-amine, 
 6-[2-fluoro-6-(methylsulfonyl)phenoxy]-N-(5-methylpyrazin-2-yl)-quinazolin-4-yl-amine, 
 6-[2-chloro-6-(cyclopropylsulfonyl)-phenoxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazol in-4-yl-amine, 
 6-[2-fluoro-6-(methylsulfonyl)phenoxy]-N-1H-pyrazol-3-ylquinazolin-4-yl-amine, 
 6-[3-cyclopropylpyridin-2-yl]oxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 [2-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)-3-(trifluoromethyl)phenyl)methanol, 
 6-[2-fluoro-6-(methylsulfonyl)phenoxy]-N-pyridazin-3-ylquinazolin-4-yl-amine, 
 N-(5-chloropyrazin-2-yl)-6-[2-fluoro-6-(methylsulfonyl)-phenoxy]quinazolin-4-yl-amine, 
 [3,5-difluoro-4-({4-[(1-methyl-1H-pyrazol-3-yl)-amino]quinazolin-6-yl}oxy)phenyl]methanol, 
 3-fluoro-2-({4-[(1-methyl-1H-pyrazol-5-yl)amino]-quinazolin-6-yl}oxy)benzonitrile, 
 6-[4-methyl-2-(methylsulfonyl)phenoxy]-N-(1-methyl-1H-pyrazol-3-yl)quinazolin-4-yl-amine, 
 6-(2,6-difluorophenoxy)-N-(1-methyl-pyrazol-3-yl)-quinazolin-4-yl-amine, 
 1-[3-methyl-2-([4-[(1-methyl-pyrazol-3-yl)amino]-quinazol in-6-yl]oxy)phenyl]ethanone, 
 6-[2-(fluoromethyl)-6-(methylsulfonyl)phenoxy]-N-(1-methyl-pyrazol-3-yl)quinazolin-4-yl-amine, 
 3-methyl-2-({4-[(1-methyl-pyrazol-3-yl)amino]-quinazolin-6-yl}oxy)benzonitrile, Cyclopropyl[3-fluoro-2-([4-[{1-methyl-pyrazol-3-yl}-amino]-quinazolin-6-yl]oxy)phenyl]methanone, 
 6-[2-fluoro-6-(methoxymethyl)phenoxy]-N-(1-methyl-pyrazol-3-yl)quinazolin-4-yl-amine, 
 [6-(5-chloro-3-fluoropyridin-2-yloxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 [6-(3-fluoropyridin-2-yloxy)-quinazolin-4-yl]-(1-methyl-1H-pyrazol-3-yl)-amine, 
 6-[2-methyl-6-(methylsulfonyl)-phenoxy]-N-(1-methyl-pyrazol-3-yl)quinazolin-4-yl-amine, 
 6-[2-(fluoromethyl)-6-(methylsulfonyl)phenoxy]-N-(1H-pyrazol-3-yl)quinazolin-4-yl-amine [or] and 
 [6-(2-fluoro-6-(methanesulfonamide)phenoxy)-quinazolin-4-yl]-(1-methyl-1H-1-pyrazol-3-yl)-amine. 
 
     
     
       6. A pharmaceutical composition comprising a compound in accordance with  claim 1  in combination with a pharmaceutically acceptable carrier.